Design, preparation and biological evaluation of libraries of marocyclic delta opioid receptor agonists for the treatment of pain

本研究计划的总体目标是提供新型肽类阿片受体激动剂用于治疗慢性疼痛。虽然在过去的30年里已经开发了许多多肽和非多肽DOPr激动剂，但很少有化合物达到临床试验，最重要的是，现在没有一种化合物被批准用于临床使用。

The overall goal of this research proposal is to provide novel peptide-based DOPr (delta opioid receptor) agonists for the treatment of chronic pain. Although numerous peptide and non-peptide DOPr agonists have been developed over the past 30 years, very few compounds have reached clinical trials and, most importantly, nowadays none of them have been approved for clinical use. Originality and novelty of this research proposal relies on the fact that we will synthesize libraries of novel cyclic enkephalin analogs which will ultimately afford drug-like molecules with better stability, enhanced delivery and greater selectivity toward DOPr. As a matter of fact, we already have synthesized such macrolactams with improved affinity for DOPr and our industrial collaborator, Cyclenium Pharma, will help us preparing biased libraries of cyclic peptides structurally related to our already potent molecules. Furthermore, our computational analysis of structure-activity and structure-selectivity relationships and PET imaging approaches will assist us during the design of the libraries.